A rare genetic variant may drive recurrent angioedema attacks in a 51-year-old woman with normal levels and function of the C1-esterase inhibitor protein, Angioedema News reported.
The patient suffered severe swelling episodes for 13 years despite trying multiple therapies.
Angioedema causes sudden swelling in the deeper layers of skin or mucous membranes, frequently striking the face, lips, tongue, or throat. In conditions like hereditary angioedema and acquired angioedema, swelling stems from bradykinin, a molecule that makes blood vessels leak fluid into surrounding tissues.
The woman experienced recurrent swelling affecting her face, arms, legs, and genital area over 13 years, often accompanied by severe abdominal pain. Each attack lasted two to three days.
Plasma Exchange Reduces Attack Frequency After Medication Failure
Antihistamines, the asthma medication omalizumab, and immunosuppressants such as cyclosporine and corticosteroids failed to control her swelling. Blood tests confirmed normal C1-INH protein levels and function, while autoimmune evaluations yielded negative results.
Doctors suspected bradykinin-mediated angioedema and started therapeutic plasma exchange in 2021. The procedure removes and replaces plasma to clear disease-driving substances from the blood.
Therapeutic plasma exchange every four weeks dropped her attack frequency from two or three per month to one every month or two, and her hives vanished. However, catheter complications interrupted the regimen, and clinicians discontinued the procedure after three years.
Weekly infusions of plasma-derived C1-INH concentrate completely stopped her swelling in February 2025, but episodes returned within two weeks of stopping treatment. She began taking Orladeyo in December 2025. The oral medication blocks plasma kallikrein, an enzyme involved in bradykinin production, keeping her free of swelling attacks over eight months of follow-up.
MYOF Gene Variant Identified Through Genetic Testing
Researchers performed genetic testing to uncover the root cause of her condition and identified a rare variant, N267D, in the MYOF gene. This gene provides instructions for making myoferlin, a protein critical for blood vessel function.
The variant was also detected in several symptom-free relatives, meaning further laboratory work remains necessary to confirm its role. Examinations revealed fewer tiny blood vessels around her fingernails and signs of new vessel growth, mirroring abnormalities seen in hereditary angioedema patients carrying a different MYOF variant.
Her blood levels of VEGF-A, a protein tied to blood vessel growth, ran higher than the average measured in a small group of healthy people. Computer modeling indicated the variant might alter how myoferlin interacts with cell membranes and recycles specific receptors in endothelial cells.
“This case integrates converging clinical, therapeutic, vascular, genetic, and structural evidence supporting a bradykinin-mediated endothelial disorder,” the researchers wrote in the Annals of Allergy, Asthma & Immunology.
“Functional studies are now required to determine whether this variant directly alters myoferlin-dependent membrane trafficking and endothelial barrier regulation,” the researchers added.
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